Methods of electrotransport drug delivery

ABSTRACT

A reservoir and a family of reservoirs are provided which are designed to be used with a single controller to provide a wide range of therapeutic drug delivering regimens while maintaining many of the same reservoir configurations and drug formulations. A method of making a reservoir and a family of reservoirs and incorporating them into an electrotransport system is disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/214,246, filed Aug. 29, 2005, which is a continuation of U.S. patentapplication Ser. No. 10/609,211, filed on Jun. 27, 2003, which isincorporated by reference and which claims benefit from U.S. provisionalapplication Ser. No. 60/392,890 filed Jun. 28, 2002, which is alsoincorporated herein by reference.

BACKGROUND

This invention relates generally to electrotransport drug delivery. Moreparticularly, the invention relates to a therapeutic agent-containingreservoir and to an interrelated family of therapeutic agent-containingreservoirs for use in an electrotransport drug delivery device such thateach reservoir is capable of delivering a different predetermined dosageof a therapeutic agent. The invention further includes electrotransportdevices which are useable with one or more of the reservoirs.

The delivery of drugs through the skin provides many advantages.Primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences—e.g., gastrointestinal irritation and thelike—are eliminated as well. Transdermal drug delivery also makespossible a high degree of control over blood concentrations of anyparticular drug.

However, many drugs are not suitable for passive transdermal drugdelivery because of their size, ionic charge characteristics andhydrophilicity. One method of achieving transdermal administration ofsuch drugs is the use of electrical current to actively transport drugsinto the body through intact skin. The method of the present inventionrelates to such iontophoresis, which is an example of such anadministration technique.

Herein the terms “electrotransport”, “iontophoresis”, and“iontophoretic” are used to refer to the delivery of pharmaceuticallyactive agents through a body surface by means of an appliedelectromotive force to an agent-containing reservoir. The agent may bedelivered by electromigration, electroporation, electroosmosis or anycombination thereof. Electroosmosis has also been referred to aselectrohydrokinesis, electro-convection, and electrically inducedosmosis. In general, electroosmosis of a species into a tissue resultsfrom the migration of solvent in which the species is contained, as aresult of the application of electromotive force to the therapeuticspecies reservoir, which results in solvent flow induced byelectromigration of other ionic species. During the electrotransportprocess, certain modifications or alterations of the skin may occur suchas the formation of transiently existing pores in the skin, alsoreferred to as “electroporation”. Any electrically assisted transport ofspecies enhanced by modifications or alterations of the body surface(e.g., formation of pores in the skin) are also included in the term“electrotransport” as used herein. Thus, as used herein, the terms“electrotransport”, “iontophoresis” and “iontophoretic” refer to (a) thedelivery of charged drugs or agents by electromigration, (b) thedelivery of uncharged drugs or agents by the process of electroosmosis,(c) the delivery of charged or uncharged drugs by electroporation, (d)the delivery of charged drugs or agents by the combined processes ofelectromigration and electroosmosis, and/or (e) the delivery of amixture of charged and uncharged drugs or agents by the combinedprocesses of electromigration and electroosmosis.

Systems for delivering ionized drugs through the skin have been knownfor some time. British Patent Specification No. 410,009 (1934) describesan iontophoretic delivery device which overcame one of the disadvantagesof the early devices, namely, the need to immobilize the patient near asource of electric current. The device was made by forming, from theelectrodes and the material containing the drug to be delivered, agalvanic cell which itself produced the current necessary foriontophoretic delivery. This device allowed the patient to move aroundduring drug delivery and thus required substantially less interferencewith the patient's daily activities than previous iontophoretic deliverysystems.

In present day electrotransport devices, at least two electrodes areused simultaneously. Both of these electrodes are disposed so as to bein intimate electrical contact with some portion of the skin of thebody. One electrode, called the active or donor electrode, is theelectrode from which the drug is delivered into the body. The otherelectrode, called the counter or return electrode, serves to close theelectrical circuit through the body. In conjunction with the patient'sskin, the circuit is completed by connection of the electrodes to asource of electrical energy, e.g., a battery, and usually to circuitrycapable of controlling current passing through the device. If the ionicsubstance to be driven into the body is positively charged, then thepositive electrode (the anode) will be the active electrode and thenegative electrode (the cathode) will serve as the counter electrode,completing the circuit. If the ionic substance to be delivered isnegatively charged, then the cathodic electrode will be the activeelectrode and the anodic electrode will be the counter electrode.

Existing electrotransport devices additionally require a reservoir orsource of the pharmaceutically active agent which is to be delivered orintroduced into the body. Such drug reservoirs are connected to anelectrode, i.e., an anode or a cathode, of the electrotransport deviceto provide a fixed or renewable source of one or more desired species oragents. A reservoir would include a reservoir matrix or gel whichcontains the agent and a reservoir housing which physically contains thereservoir matrix or gel. In addition to the drug reservoir, anelectrolyte-containing counter reservoir is generally placed between thecounter electrode and the body surface. Typically, the electrolytewithin the counter reservoir is a buffered saline solution and does notcontain a therapeutic agent. In early electrotransport devices, thedonor and counter reservoirs were made of materials such as paper (e.g.,filter paper), cotton wadding, fabrics and/or sponges which could easilyabsorb the drug-containing and electrolyte-containing solutions. In morerecent years however the use of such reservoir matrix materials hasgiven way to the use of hydrogels composed of natural or synthetichydrophilic polymers. See for example, Webster, U.S. Pat. No. 4,383,529and Venkatraman, U.S. Pat. No. 6,039,977. Such hydrophilic polymericreservoirs are preferred from a number of standpoints, including theease with which they can be manufactured, the uniform properties andcharacteristics of synthetic hydrophilic polymers, their ability toquickly absorb aqueous drug and electrolyte solutions, and the ease withwhich these materials can be handled during manufacturing. Such gelmaterials can be manufactured to have a solid, non-flowablecharacteristic. Thus, the reservoirs can be manufactured having apredetermined size and geometry.

Generally, the geometry of a reservoir can be described in terms ofthree parameters:

(1) the average cross-sectional area of the reservoir (“A_(RES)”),defined as the arithmetic mean of reservoir cross-sectional areasmeasured at a number of different distances from and parallel to thebody surface;

(2) the average thickness of the reservoir; and

(3) the body surface contact area (“A_(BODY)”).

References to reservoir housing configuration and the above parametersinclude not only the parameters of the physical reservoir housing, butalso include the physical parameters of the reservoir gel or matrix aswell.

Electrotransport drug delivery devices having a reusable controllerdesigned to be used with more than one drug-containing unit have beendescribed. The drug-containing unit can be disconnected from thecontroller when the drug becomes depleted and a fresh drug-containingunit can then be connected to the controller. The drug-containing unitincludes the reservoir housing, the reservoir matrix, and associatedphysical and electrical elements which enable the unit to be removablyconnected, both mechanically and electrically to the controller. In thisway, the relatively more expensive hardware components of the device(e.g., the batteries, the light-emitting diodes, the circuit hardware,etc.) can be contained in the reusable controller. The relatively lessexpensive donor reservoir and counter reservoir may be contained in thesingle use, disposable drug containing unit. See, Sage et al., U.S. Pat.No. 5,320,597; Sibalis, U.S. Pat. Nos. 5,358,483 and 5,135,479.Electrotransport devices having a reusable electronic controller withsingle use/disposable drug units have also been proposed forelectrotransport systems comprised of a single controller adapted to beused with a plurality of different disposable drug units. For example,Johnson et al., WO 96/38198 discloses the use of such reusableelectrotransport controllers which can be connected to drug units fordelivering the same drug, but at different dosing levels, (e.g., a highdose drug unit and a low dose drug unit) which can be connected to thesame electrotransport controller. Although these systems go far inreducing the overall cost of transdermal electrotransport drug delivery,further cost reductions are needed in order to make this mode of drugdelivery more competitive with traditional delivery methods such as bydisposable syringe.

SUMMARY

The present invention provides a method of modifying the geometry oftherapeutic agent-containing reservoirs to create a family of reservoirconfigurations. This modification is accomplished by altering the threereservoir parameters described above. The actual drug formulation usedfor the reservoir composition for each reservoir in the family is thesame. Only the reservoir geometry is modified to achieve desiredperformance characteristics.

The present invention includes a method of making both reservoirs andelectrotransport systems in which the reservoirs have been modifiedindividually and as part of a family of reservoirs based upon the methodmodification of the reservoir parameters as described herein.

The present invention further provides a method of varying the electrodearea (“A_(ELECTRODE)”) in conjunction with other reservoir parameters inorder to design a reservoir configuration best suited for a particularpurpose.

Accordingly, it is a primary aspect of the invention to provide a familyof therapeutic agent-containing reservoirs, each having differentreservoir parameters but the same reservoir drug composition, for use inan electrotransport drug delivery device. It is another aspect of theinvention to provide an electrotransport system that includes at leastone of reservoir of such a family of reservoirs.

In accordance with one embodiment of the invention, an electrotransportsystem for delivering a therapeutic agent transdermally is provided. Thesystem is comprised of an electronic controller which contains anelectronic circuit for controlling, and optionally supplying, theelectrotransport current applied by the system. Also included is afamily of at least two different therapeutic agent-containing units,each of the two units being electrically connectable to the controllerto form a complete electrotransport delivery device. Each of the twounits has a therapeutic agent-containing reservoir with a drug reservoircomposition, an average thickness, and an average cross-sectional area(A_(RES)) that is measured in a plane that is roughly parallel to thebody surface through which the agent is to be delivered, and an A_(BODY)this the same as the A_(RES) unless the A_(BODY) has been reduced by theuse of a mask.

All of the following discussions regarding a family of reservoirs makereference to two drug reservoirs. However, it should be understood thata family of reservoirs can be comprised of any number of drugreservoirs, each one meeting the configuration requirements for thatembodiment.

A first embodiment of the invention has the following configuration:

-   -   a. the reservoir thickness of each of the two different        agent-containing units is the same;    -   b. the reservoir composition of each of the two different        agent-containing units is the same; but    -   c. the average cross-sectional area (A_(RES)) of one reservoir        is substantially different than the average cross-sectional area        of the other reservoir.

Thus, the unit having the reservoir with the substantially smalleraverage cross-sectional area would be a slower delivering drug unitwhereas the unit having the larger average cross-sectional area would bea faster delivering drug unit.

The current supplied by the controller to each different drug reservoirmay need to be altered in order to provide the proper current densitywhich varies with the A_(BODY). The means for making such alterationsand for recognizing which drug unit is attached to the controller areknown to one skilled in the art.

A second embodiment of the invention has the following configuration:

-   -   the average cross-sectional areas of the reservoirs in the two        agent-containing units are the same,    -   the agent reservoir compositions of the two different        agent-containing units are the same, but    -   the thickness of one of the two reservoirs in the        agent-containing unit is substantially different than the        thickness of the reservoir in the other agent-containing unit.

The two units would deliver at initially the same rate. However, theunit with the thinner reservoir would deliver for a shorter period oftime and thus be a low dose unit and the reservoir having the thickerreservoir would deliver for a longer period of time and be a high dosedrug unit.

It will be appreciated that the agent reservoir compositions in both ofthe two above-described embodiments are the same for each of the twodifferent drug units. A number of issues have to be considered whendeveloping different composition, even if these compositions aresomewhat similar. Thus it is best to avoid developing more compositionsthan are needed. Thus, the cost of developing an electrotransportdelivery device for delivering a drug at different dosing levels (e.g.,high dose and low dose), is substantially reduced since only a singleagent reservoir composition is required to be developed.

The invention has particular utility in those electrotransport systemshaving an electronic controller with an operational life that issubstantially longer than the operational life of the therapeuticagent-containing unit (e.g., an electrotransport system comprised of areusable electronic controller which is adapted to be connected,sequentially, with a plurality of single use/disposable drug units).

In one embodiment, an agent-containing reservoir for incorporation intoan electrotransport drug delivery system is provided. The reservoir hasbeen configured to optimize drug delivery, biocompatibility, andelectrochemistry. The reservoir is adapted to be placed inagent-transmitting contact with a subject body surface for deliveringthe agent through the body surface by means of an electrotransportcurrent (i) applied to the reservoir via a reservoir-contactingelectrode. The reservoir thus provided is permeable to electricallyassisted electrotransport of the agent and has:

-   -   a predetermined volume that holds a quantity of the agent        sufficient to achieve therapeutically effective delivery of the        agent during the entire intended duration of use, wherein the        predetermined volume for a given reservoir thickness is defined        by the reservoir average cross-sectional area A_(RES) and the        thickness of the reservoir;    -   a surface that is placed in contact with the body of the subject        during use, the body-contacting surface having an area A_(BODY)        that provides at least one, and preferably all, of:        -   (i) a reservoir/body surface current density, I_(BODY)            (I_(BODY)=i/A_(BODY)) greater than a critical current            density level as defined herein, and        -   (ii) a drug flux j that is biocompatible;    -   (c) a surface in contact with the electrode, the        electrode-contacting surface having an area A_(ELECTRODE) that        provides a reservoir/electrode current density I_(ELECTRODE),        wherein I_(ELECTRODE)=i/A_(ELECTRODE), that results in at least        one of:        -   (i) a desired electrochemical reaction along the            electrode-contacting surface, and        -   (ii) avoidance of undesired polarization along the            electrode-contacting surface;        -   and wherein A_(BODY) and A_(RES) may be different.

One embodiment would comprise a system of drug containing units in whichthe reservoir A_(RES) varies but in which the A_(BODY) is altered to bethe same by the use of different sized masks. This enables identicaldrug delivery but different sized reservoirs (assuming constantcurrent).

In another embodiment, an electrotransport system for delivering anagent through a body surface is provided. The system comprises at leasttwo different types of agent-containing units and a controller. Thedifferent agent-containing units contain different amounts of a singleformulation of the therapeutic agent to achieve different dosing levels.Each of the reservoirs in the different types of agent-containing unitshave:

-   -   (a) a predetermined volume,    -   (b) a surface that is placed in contact with a body surface of a        subject during use,    -   (c) a surface which is in contact with the electrode, and    -   (d) a reservoir average cross-sectional area A_(RES), as        described above, wherein        -   A_(BODY) and A_(RES) are different between the distinct            agent-containing unit types.

The controller generates and/or controls an electrotransport current (i)and is adapted to be sequentially and removably attachable to a seriesof agent-containing units, one agent-containing unit at a time. Thecontroller applies the electrotransport current (i) to respectivereservoirs in the different types of agent-containing units via areservoir-contacting electrode.

The system may further comprise a coupler for separably coupling thecontroller to any one agent-containing reservoir and providingelectrical and mechanical connection of the controller to theagent-containing reservoir. The controller may be capable of providing asingle current output or multiple current outputs. According to certainembodiments, different types of therapeutic agent-containing reservoirsprovide a signal to the controller related to the dosage of thetherapeutic agent to be delivered. The controller may include areceiving means for receiving the signal and selecting the output of thecontroller in response to the signal. The signal may include an opticalsignal. The signal may include a coded signal from an electromechanicalconnector, the electromechanical connector functioning to mechanicallyand electrically couple the therapeutic agent-containing reservoir tothe controller. In some embodiments, the controller may include acapacitance sensor which senses a capacitance signal provided by thetherapeutic agent-containing reservoir.

Additional aspects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective exploded view of one embodiment of anelectrotransport drug delivery system which may be used in conjunctionwith a reservoir according to the present invention.

The two reservoirs in FIGS. 2A, 2B and 2C, 2D depict a variable-A_(RES),variable-A_(BODY), and constant-thickness reservoir family. FIGS. 2A and2B are respectively top-plan and cross-sectional views of the firstreservoir having a thickness T₁ and relatively large A_(RES) andA_(BODY). FIGS. 2C and 2D are respectively top-plan and cross-sectionalviews of the second reservoir also having the same thickness T₁ as FIGS.2A and 2B, but a relatively small A_(RES) and A_(BODY). The relativelylarge diameter of the reservoir and body contact area are shown in FIGS.2A and 2B and are indicated as D₁. The relatively small diameter of thereservoir and body contact area are shown in FIGS. 2C and 2D and areindicated as D₂.

The two reservoirs in FIGS. 3A, 3B and 3C, 3D depict avariable-thickness, constant-A_(RES) and constant-A_(BODY) family ofreservoirs. FIGS. 3A and 3B are respectively top-plan andcross-sectional views of the first reservoir having a relatively largethickness T₂. FIGS. 3C and 3D are respectively top-plan andcross-sectional views of such a reservoir having a relatively smallthickness T₃, and the same A_(RES) and A_(BODY) as shown in FIGS. 3A and3B.

FIG. 4A and FIG. 4B are respectively top-plan and cross-sectional viewsof a reservoir including an A_(BODY)-reducing mask.

FIG. 5 is a cross-sectional view of a reservoir including anA_(BODY)-reducing mask and an inert filler.

FIG. 6 depicts a reservoir including an A_(BODY)-reducing mask and anelectrode shaped to provide an increased A_(ELECTRODE).

FIGS. 7A and 7B depict two reservoirs from a family of reservoirs whichare essentially the same in all physical and chemical parameters, butwhich provide for varying drug delivery based upon the use of a mask (asshown in FIG. 7 b) which decreases the A_(BODY) (Assuming the sameI_(d))

DETAILED DESCRIPTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular drugs, drugsalts, resins, reservoirs or electrotransport delivery systems, as suchmay vary.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a reservoir” includes one or more reservoirs, reference to“a drug” or “a therapeutic agent” includes a mixture of two or moredrugs or agents, reference to “a filler material” includes reference toone or more filler materials, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The term “current” or “i” is intended to include both constant current,continuously varying current, and pulsed current, e.g., a square wavecurrent alternating between an “off” state and an “on” state, whereineach “on” state may be constant, varying, greater than, less than or thesame as the previous “on” state. Preferably, the current is a constantnon-varying DC current or a pulsed DC current in which “on” states arethe same constant current.

A “biocompatible” I_(BODY) is a current density less than or equal tothe maximum current density that can be tolerated by a patient orsubject, e.g., less than that which produces intolerable sensation, skinirritation or damage. In the context of the invention disclosed herein,a biocompatible I_(BODY) is less than or equal to the maximum I_(BODY)that causes a tolerable degree of sensation and/or irritation. Inaddition, a biocompatible I_(BODY) is one which effectuates sufficientdrug delivery to achieve a therapeutic effect, yet less drug deliverythan that which would be toxic to the patient or subject. Thebiocompatibility of I_(BODY) depends on a number of factors, includingthe nature of the therapeutic agent, the level of current applied toeffect delivery, the duration of drug delivery, and the like. Usingstandard toxicological and clinical methods, a person having ordinaryskill in the art will be able to determine what a biocompatible I_(BODY)would be for a particular application. A biocompatible I_(BODY) istypically less than about 0.2 mA/cm², preferably less than about 0.1mA/cm², for chronic drug delivery, e.g., over a period of approximately12 to 72 hours. For acute drug delivery I_(BODY) is typically less thanabout 1 mA/cm², preferably less than about 0.3 mA/cm². Drug flux isdefined as the amount of drug delivered per unit of body surface areaper unit time. Accordingly, a biocompatible drug flux j is the fluxproduced by a biocompatible I_(BODY) and that is within a dosage rangethat produces a therapeutic effect.

The term “mask” is intended to mean a device which can be used to modifythe body surface contact area, A_(BODY), of an agent-containingreservoir. Thus, a mask may include any material that is essentiallyelectrically impermeable and thus restricts the area that current canflow to that portion of the A_(RES) that is not covered by the mask.Preferred materials for the mask include polymeric materials, such aspolyesters, polyolefins, polysilicones, polybutylenes, cellulosics,polyvinyl acetates, polycarbonates, and the like. The mask may be amulti-laminate construction having a body surface-contacting adhesivelayer.

The term “inert filler material” refers to a material havingsubstantially no tendency to interact with the therapeutic agent orother excipients in the reservoir formulation, which means that such aninert filler material will not bind, absorb, adsorb or react chemicallywith any significant quantity of therapeutic agent or excipient. Inaddition, the inert filler will not undergo any substantialelectrochemical reaction. The material will generally be particulate orfibrous, or it may be comprised of a glass or ceramic bead, polymericmesh, gas-filled void, or the like.

By the term “dosage” is meant the amount of agent delivered from anelectrotransport delivery device. The term is intended to encompass theamount of drug delivered per unit of time, the total amount of drugdelivered over a period of time, the duration of time over which thedrug is to be delivered, and the like.

The following synonymous terms, “pharmaceutically active agent”, “drug”,“agent”, or “therapeutic agent”, as used herein, mean any chemicalmaterial or compound which induces a desired local or systemic effect ina subject, and is capable of being delivered to the subject byelectrotransport.

Drugs, which are therapeutic or otherwise are active agents useful inconnection with the present invention, include any pharmaceuticalcompound or chemical that is capable of being delivered byelectrotransport. In general, this includes agents in all of the majortherapeutic areas including, but not limited to, anti-infectives such asantibiotics and antiviral agents, analgesics including fentanyl,sufentanil, remifentanil, and other opioids, buprenorphine and analgesiccombinations, anesthetics, anorexics, antiarthritics, antiasthmaticagents such as terbutaline, anticonvulsants, antidepressants,antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatoryagents, antimigraine preparations, antimotion sickness preparations suchas scopolamine and ondansetron, antinauseants, antineoplastics,antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics,antispasmodics, including gastrointestinal and urinary anticholinergics,sympathomimetics, xanthine derivatives, cardiovascular preparationsincluding calcium channel blockers such as nifedipine, beta-blockers,beta-agonists such as dobutamine and ritodrine, antiarrythmics,antihypertensives such as atenolol, ACE inhibitors such as rinitidine,diuretics, vasodilators, including general, coronary, peripheral andcerebral, central nervous system stimulants, cough and coldpreparations, decongestants, diagnostics, hormones such as parathyroidhormone, bisphosphoriates, hypnotics, immunosuppressives, musclerelaxants, parasympatholytics, parasympathomimetics, prostaglandins,psycho stimulants, sedatives and tranquilizers. The invention is alsouseful in conjunction with the electrotransport delivery of proteins,peptides and fragments thereof, whether naturally occurring, chemicallysynthesized or recombinantly produced.

As noted above, the invention is also useful in the controlled deliveryof peptides, polypeptides, proteins and other such species. Thesesubstances typically have a molecular weight of at least about 300daltons, and more typically have a molecular weight of at least about300 to 40,000 daltons. Specific examples of peptides and proteins inthis size range include, without limitation, LHRH, LHRH analogues suchas goserelin, buserelin, gonadorelin, napharelin and leuprolide, GHRH,GHRF, insulin, insultropin, calcitonin, octreotide, endorphin, TRH,NT-36 (chemical name:N-[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (e.g., HGH, HMG, desmopressin acetate,etc), follicle luteoids, αANF, growth factors such as growth factorreleasing factor (GFRF), βMSH, somatostatin, bradykinin, somatotropin,platelet-derived growth factor, asparaginase, bleomycin sulfate,chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin(ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor),glucagon, HCG, hirulog, hyaluronidase, interferon, interleukins,menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase,tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTHanalogues, ANP, ANP clearance inhibitors, angiotensin II antagonists,antidiuretic hormone agonists, bradykinin antagonists, CD4, ceredase,enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophicfactors, colony stimulating factors, parathyroid hormone and agonists,parathyroid hormone antagonists, prostaglandin antagonists, pentigetide,protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics,TNF, vaccines, vasopressin antagonists analogues, alpha-1 antitrypsin(recombinant), and TGF-beta.

Additional agents include fentanyl hydrochloride, pilocarpine nitrate,lidocaine hydrochloride, hydrocortisone derivatives, sodium salicylate,acetic acid, fluoride anion, lithium, antibiotics such as penicillin andcephalosporin and dexamethasone sodium phosphate, hydromorphone,diazepam salts, antihypertensive agents, bronchodilator agents, peptidehormone and regulatory agents and proteins.

It will be appreciated by those working in the field that the presentreservoir system can be used in conjunction with a wide variety ofelectrotransport drug delivery systems, as the system is not limited inany way in this regard. For examples of electrotransport drug deliverysystems, one can refer to U.S. Pat. Nos. 5,147,296 to Theeuwes et al.,5,080,646 to Theeuwes et al., 5,169,382 to Theeuwes et al., and5,169,383 to Gyory et al., as well as to U.S. Pat. Nos. 5,224,927,5,224,928, 5,246,418, 5,320,597, 5,358,483 and 5,135,479, and UK PatentApplication No. 2 239 803.

FIG. 1 illustrates a representative electrotransport delivery devicethat may be used in conjunction with the present reservoir system.Device 10 comprises an upper housing 16, a circuit board assembly 18, alower housing 20, anode electrode 22, cathode electrode 24, anodereservoir 26, cathode reservoir 28 and body surface-compatible adhesive30. Upper housing 16 has lateral wings 15 which assist in holding device10 on the body surface of a subject, e.g., skin, mucosal tissue, and thelike. Upper housing 16 is preferably composed of an injection moldableelastomer (e.g., ethylene vinyl acetate). Printed circuit board assembly18 comprises an integrated circuit 19 coupled to discrete components 40and battery 32. Circuit board assembly 18 is attached to housing 16 byposts (not shown in FIG. 1) passing through openings 13 a and 13 b, theends of the posts being heated/melted in order to heat stake the circuitboard assembly 18 to the housing 16. Lower housing 20 is attached to theupper housing 16 by means of adhesive 30, the upper surface 34 ofadhesive 30 being adhered to both lower housing 20 and upper housing 16including the bottom surfaces of wings 15.

Shown (partially) on the underside of circuit board assembly 18 is abutton cell battery 32. Other types of batteries may also be employed topower device 10.

The device 10 is generally comprised of battery 32, electronic circuitry19, 40, electrodes 22, 24, and drug reservoirs 26, 28, all of which areintegrated into a self-contained unit. The outputs (not shown in FIG. 1)of the circuit board assembly 18 make electrical contact with theelectrodes 24 and 22 through openings 23, 23′ in the depressions 25, 25′formed in lower housing 20, by means of electrically conductive adhesivestrips 42, 42′. Electrodes 22 and 24, in turn, are in direct mechanicaland electrical contact with the top sides 44′, 44 of drug reservoirs 26and 28. The bottom sides 46′, 46 of drug reservoirs 26, 28 contact thesubject body surface through openings 29′, 29 in adhesive 30.

Device 10 optionally has a feature which allows the subject toself-administer a dose of drug by electrotransport. Upon depression ofpush button switch 12, the electronic circuitry on circuit boardassembly 18 delivers a predetermined DC current to theelectrode/reservoirs 22, 26 and 24, 28 for a delivery interval ofpredetermined length. The push button switch 12 is conveniently locatedon the top side of device 10 and is easily actuated through clothing. Adouble press of the push button switch 12 within a short time period,e.g., three seconds, is preferably used to activate the device fordelivery of drug, thereby minimizing the likelihood of inadvertentactuation of the device 10. Preferably, the device transmits to the usera visual and/or audible confirmation of the onset of the drug deliveryinterval by means of light-emitting diode (LED) 14 becoming lit and/oran audible sound signal from, e.g., a “beeper.” Drug is deliveredthrough the subject's body surface by electrotransport, e.g., on thearm, over the predetermined delivery interval.

Anodic electrode 22 is preferably comprised of silver and cathodicelectrode 24 is preferably comprised of silver chloride. Both reservoirs26 and 28 are preferably comprised of polymer hydrogel materials.Additional components, such as inert fillers, may be added to reservoirs26 and 28. Electrodes 22, 24 and reservoirs 26, 28 are retained by lowerhousing 20.

The push button switch 12, the electronic circuitry on circuit boardassembly 18 and the battery 32 are adhesively “sealed” between upperhousing 16 and lower housing 20. Upper housing 16 is preferably composedof rubber or other elastomeric material. Lower housing 20 is preferablycomposed of a plastic or elastomeric sheet material (e.g., polyethylene)which can be easily molded to form depressions 25, 25′ and cut to formopenings 23, 23′. The assembled device 10 is preferably water resistant(i.e., splash proof) and is most preferably waterproof. The system has alow profile that easily conforms to the body, thereby allowing freedomof movement at, and around, the wearing site. Reservoirs 26 and 28 arelocated on the body surface-contacting side of the device 10 and aresufficiently separated to prevent accidental electrical shorting duringnormal handling and use.

Device 10 adheres to the patient's body surface by means of a peripheraladhesive 30 which has upper side 34 and body-contacting side 36.Adhesive side 36 has adhesive properties which assures that device 10remains in place on the body during normal user activity, and yetpermits reasonable removal after the predetermined (e.g., 24-hour) wearperiod. Upper adhesive side 34 adheres to lower housing 20 and retainsthe electrodes and drug reservoirs within housing depression 25, 25′ aswell as retains lower housing 20 attached to upper housing 16.

Reservoirs 26 and 28 generally comprise a gel with the drug solutionuniformly dispersed in at least one of reservoirs 26 and 28. Drugconcentrations in the range of approximately 1×10⁻⁴ M to 1.0 M or morecan be used, with drug concentrations in the middle portion of therange, i.e., 1 mM to 0.1 M, being preferred. Suitable polymers for thereservoir may comprise essentially any nonionic synthetic and/ornaturally occurring polymeric materials. A reservoir which is polar innature is preferred when the active agent is polar and/or capable ofionization, so as to enhance agent solubility. Optionally, the gelpolymer will be water-swellable. Examples of suitable synthetic polymersinclude, but are not limited to, poly(acrylamide), poly(2-hydroxyethylacrylate), poly(2-hydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone),poly(n-methylol acrylamide), poly(diacetone acrylamide),poly(2-hydroxylethyl methacrylate), poly(vinyl alcohol) and poly(allylalcohol). Hydroxyl functional condensation polymers (i.e., polyesters,polycarbonates, polyurethanes) are also examples of suitable polarsynthetic polymers. Polar naturally occurring polymers (or derivativesthereof) suitable for use as the gel polymer are exemplified by, but notlimited to cellulose ethers, methyl cellulose ethers, cellulose andhydroxylated cellulose, methyl cellulose and hydroxylated methylcellulose, gums such as guar, locust, karaya, xanthan, gelatin, andderivatives thereof. Ionic polymers can also be used for the reservoirprovided that the available counterions are either drug ions or otherions that are oppositely charged relative to the active agent.

A reservoir disclosed and claimed herein for use in such a device has apredetermined volume and is designed to contain an amount of an drugsufficient to achieve a therapeutic effect. The total amount of drug,D_(T), incorporated into a reservoir of the invention may generally bedetermined using the following relationship:D _(T) =D _(E) +D _(M)+(the greatest of D _(F) , D _(C) and D _(P)).

In the above relationship, D_(E) is the amount of drug needed to achievea therapeutic effect for a desired period of time. D_(M) is the amountof drug needed to compensate for engineering uncertainty. Suchuncertainty may arise from manufacturing limitations, for example, fromweighing ingredients, filling reservoir cavities, and the like. Theamount D_(M) is typically calculated from the drug content specificationlimit, which is generally in the range of from about ±5% to about ±25%of the D_(T).

D_(F) is the amount of drug needed to maintain constant drug flux, i.e.,flux independent of the concentration of drug in the reservoir. If, forexample, the drug concentration were to drop to a level at which flux isdependent on drug concentration, flux would diminish with drugconcentration as drug is depleted from the reservoir with delivery tothe subject. Under these circumstances, the current supplied from thebattery would have to be increased to maintain a flux rate desired toachieve a therapeutic effect. This would cause not only a more rapidpower drain of the source but also an increase in I_(BODY), eventuallyto a level above biocompatibility. Thus, an additional amount of drugabove D_(E) may be added to insure that the flux is independent of theagent concentration throughout the duration of drug delivery.

D_(C) is the amount of drug required to maintain conductivity of thedrug-containing reservoir. Current-driven electrotransport drug deliveryis dependent on ionized species dissolved or dispersed in the reservoir.The conductivity of the reservoir is due, at least in part, to thepresence of the ionic species contained therein. If the conductivitywere to drop sufficiently due to a decrease in the amount of drug in thereservoir, an increase in voltage would be required to maintain constantcurrent and therefore maintain agent flux at a level needed to achievethe desired therapeutic effect. If the voltage required to maintain thetarget current exceeds the voltage output capabilities of thecontroller, then the necessary current level cannot be maintained andthe desired flux of agent would not be maintained. Thus, an additionalamount of drug D_(C), in addition to D_(E), may have to be added to thereservoir to minimize the likelihood that the conductivity of thereservoir would drop below a critical level.

D_(P) is the amount of additional drug needed to avoid unwantedpolarization. In a typical electrotransport drug delivery device, theanode is silver and, during operation of the device, the silver isconverted to silver ions that are neutralized by anions, e.g., chlorideions, present in the reservoir or migrating into the reservoir from thebody. If the quantity or mobility (in units of velocity per unitelectric field strength) of the neutralizing counterions isinsufficient, then silver ions may migrate into the reservoir. Thepresence of the silver ions, in concert with the increased voltagerequired to overcome such polarization, would change the chemicalproperties, e.g., the pH, of the reservoir. Such a change in reservoirchemistry may affect the ionic character and/or stability of the drugcontained therein and, consequently, its current-driven delivery fromthe reservoir. Since therapeutic drugs are typically provided in saltform, e.g., as their chloride or hydrochloride salt, an additionalamount of drug above D_(E) may be provided to contribute counterions tothe reservoir to neutralize the silver ion formed during operation. Ingeneral, D_(P) is the amount of drug required to maintain the favoredelectrochemical reaction at the electrode, e.g., Ag+Cl⁻→AgCl+e⁻, and tominimize unwanted concentration polarization.

The total amount of drug, D_(T), that is to be placed in a reservoirprovides a constraint on the geometry of the reservoir. The reservoirmust have a large enough volume to contain a quantity of drug sufficientto achieve a therapeutic effect over the desired administration period.In addition, a reservoir must be sufficiently thin to be flexible andconform to the body surface with which it is contacted. The reservoirmust also be wearable. An electrotransport drug delivery devicecontaining a reservoir that is too thick will be difficult orundesirable to wear and may be dislodged by physical contact when worn.Moreover, if a reservoir is too thin, it will need to have a largerA_(RES) to accommodate a given volume of drug formulation, which mayresult in a I_(BODY) that is too low for efficient drug delivery.Furthermore, the reservoir must be easily manufactured withinpredetermined tolerances. The reservoir must be manufactured at areasonable cost and therefore excessively thick or thin reservoirs maybe cost-prohibitive to manufacture. Drug remaining in the reservoir uponcompletion of the therapeutic treatment period is wasted. A desire tominimize this waste also constrains the reservoir volume. Thisconsideration can be particularly important for an expensive drug, orfor a drug having high abuse potential.

The requirement for a physically and chemically stable drug formulationalso constrains the reservoir geometry. For example, undesirableprecipitation of drug during storage may be minimized by using areservoir containing a concentration of drug less than that which wouldotherwise be likely to precipitate.

For a given reservoir thickness, the maximum drug concentration possiblewill dictate the minimum A_(RES) needed for a specific drug and deliveryperiod. The upper limit of drug concentration will be the highestconcentration that can be used without the formation of precipitatesunder the conditions of use.

If this minimum A_(RES) is too large to achieve a desired currentdensity, I_(BODY), the reservoir thickness may be increased to permit areduction in A_(RES). However, if increasing the thickness is prohibitedby other factors, the contact area between the reservoir and the body(A_(BODY)) may be reduced by the use of a mask placed between thereservoir and the body. Such a reduction in the A_(BODY) would result ina higher I_(BODY).

Because A_(RES), A_(BODY), and A_(ELECTRODE) are determined by differentfactors, design of an electrotransport drug delivery system thatsimultaneously achieves optimal values for each of these designparameters is difficult. The design challenge is particularly difficultwhen the thickness of the reservoir is constrained and when the need tominimize residual drug is paramount. The invention disclosed and claimedherein provides specific design features adapted to achieve an optimalbalance between the different geometric considerations.

The thickness of a reservoir in accordance with this invention isgenerally less than 1 cm and preferably less than about 0.5 cm sincereservoirs having a thickness greater than 1 cm can more easily bemanipulated so that the reservoir has a varying cross-sectional areaalong its thickness. (For example, a reservoir could be tapered, withone end being larger in area than the other end. Typically, though notnecessarily, the smaller end would be the body contacting end. Theoverall volume can be controlled by adjusting both the larger and thesmaller diameter, while the A_(BODY) can be controlled by adjusting onlythe smaller diameter.) With reservoirs formed of polymeric gelmaterials, the reservoir thickness cannot be reduced to less than about0.1 mm due to the difficulty in handling and cutting such thinmaterials. Accordingly, the reservoirs of this invention will generallybe between about 0.1 mm to about 10 mm, preferably about 0.5 mm to about3 mm. A typical reservoir is 2 mm thick. The total amount ofdrug-contained in a formulation in a reservoir having a predeterminedthickness, will be determined by the concentration of drug in theformulation and the A_(RES).

For drug reservoirs that 1) utilize a given drug-containing formulation,2) have a predetermined thickness and 3) are designed to containdifferent total amounts of drug, they must each have a differentA_(RES). For example, two reservoirs having the same predeterminedthickness but that differ by 10-fold in the total amount of drugcontained therein, must have a 10-fold difference in their respectiveA_(RES). Such differences in A_(RES) may result in differences inA_(BODY), as well as in differences in reservoir/electrode contactsurface area (A_(ELECTRODE)).

For example, a first reservoir containing a large amount of drug mayhave an A_(BODY) greater than that of a second reservoir containing asmall amount of drug. Thus, for a given drug-delivery current, the firstreservoir (larger A_(BODY)) may have a commensurately low I_(BODY) thatmay be below a critical I_(BODY).

At least two current density zones have been recognized: one in whichdrug delivery is independent of current density; and one in which drugdelivery is dependent on current density. In essence, a plot of the rateof delivery per unit current, or Rate/i, versus I_(BODY) would show thatRate/i is highly dependent on the I_(BODY) in the range of about 0 toabout 30 μA/cm². Rate/i is moderately dependent on the I_(BODY) in therange of about 40 to about 70 μA/cm² and Rate/i is relativelyindependent of I_(BODY) in excess of about 70 μA/cm².

This change in Rate/i permits delivery of drug in the higher efficiencystate with significantly enhanced efficiency. The terms “Rate/i” and“efficiency of drug delivery” are used interchangeably herein.

The term “higher efficiency state” as used herein means the state of aparticular body or skin site in which Rate/i for that body site is atleast about 10% and preferably 20% greater than the Rate/i at the samesite prior to conversion to the higher efficiency state. The term“greater stability state” as used herein means a state of less variabledrug delivery from one of greater variability wherein the variabilityrefers to changes in the Rate/i when plotted against current density.The higher efficiency state is the result of exposure of the site to aI_(BODY) above the critical I_(BODY) for a time period longer than thecritical time, t_(c). Critical I_(BODY) for purposes of increasedstability has been found to be as low as about 40 μA/cm².

A “Critical I_(BODY)” is a current density level above which Rate/i isapproximately maximal and substantially independent of current densityoccurring at the body-contacting surface during therapeutic use of thedevice. The Critical I_(BODY) may be that current density which, whendelivered for critical time t_(c), will change or convert the transportefficiency of the body surface through which the ionic species isdelivered to a nontransitory state of higher or enhanced Rate/i. Currentdensity and the period of application of this current density are chosento maintain the higher efficiency species delivery state of the bodysurface.

The precise I_(BODY) and critical time t_(c) needed to convert anuntreated body surface to a highly efficient state are fairly specificto the drug or therapeutic agent to be delivered. However, forelectrotransport delivery of analgesics, for example, a treatment of thebody site through which drug is to be delivered for a time period of atleast 10 milliseconds to 20 minutes or longer, e.g., 30 minutes, at anI_(BODY) of about 40 μA/cm², preferably at least about 50 μA/cm² andmost preferably about 70 μA/cm², appears to convert the body site sotreated to a highly efficient state.

The amount of drug required to achieve the predetermined dosage,depends, at least in part, on Rate/i. The Rate/i limits the minimumI_(BODY) that can be used to achieve the predetermined dosage. Thus,during a period when the skin site is in-a state of lower drug deliveryefficiency, more current may be required to deliver the predetermineddosage of drug. In order to increase the amount of current applied tomaintain the dosage, the system can be designed with a larger A_(BODY)while still taking into account the maximum biocompatible I_(BODY). Inaddition, increased current demand may decrease the life expectancy ofthe battery. It is preferred that the I_(BODY) be maintained at a levelabove the critical I_(BODY).

The volume of the reservoir required to contain sufficient drug toachieve this predetermined dosage also depends in part on: (a) theamount of drug required to insure a therapeutic level of drug can bedelivered for the duration required; and (b) the concentration of drugthat can be dissolved in the reservoir formulation.

The reservoir configuration, i.e., thickness and A_(RES), may bedesigned, for example, by determining the amount of drug formulationrequired to support the rate of delivery for a predetermined durationand the volume of the reservoir required to contain that amount of drug.Thus, for a predetermined thickness, the A_(RES) of the reservoir may becalculated based on the volume of the drug reservoir required. If theA_(RES) is greater than the A_(BODY) needed to achieve the criticalI_(BODY), a mask may be used to reduce the A_(BODY).

In addition, the A_(BODY) may be determined based on (a) the minimumdrug delivery rate that is required to achieve a therapeutic effect, (b)the rate at which the drug can be delivered per unit of current suppliedby the controller, and (c) the biocompatible I_(BODY).

FIGS. 2A-2D illustrates a constant thickness T₁ reservoir family havinga variable A_(BODY), variable A_(RES). In FIGS. 2A and 2B, reservoir 50has a housing 52 that defines the shape of the reservoir and containselectrode 54 and drug-containing gel 56. FIGS. 2C and 2D reservoir 60has a housing 62 that defines the shape of the reservoir and containselectrode 64 and drug-containing gel 66.

In FIGS. 2A and 2B, reservoir 50 has a larger A_(BODY) and A_(RES)relative to that of reservoir 60 as illustrated in FIGS. 2C and 2D. Forreservoir 50, A_(BODY) and A_(RES) are the same, each being circular inshape and having a diameter of D₁. For reservoir 60, A_(BODY) andA_(RES) are the same, each being circular in shape and having a diameterof D₂, which is smaller than the D₁ diameter of reservoir 50. Thethickness T₁ of reservoirs 50 and 60 are the same as shown in FIGS. 2Band 2D.

The drug containing gel 56 and 66 have the same formulation. However,because of the larger A_(BODY) of reservoir 50, it will deliver drug ata faster rate for any given I_(BODY).

FIGS. 3A-3D illustrate a constant-A_(BODY) and constant-A_(RES)therapeutic agent-containing reservoir family which has a variablethickness. FIGS. 3A and 3B illustrate reservoir 70 having a largethickness T₂ relative to thickness T₃ of reservoir 80 as shown in FIG.3B and 3D. The A_(BODY) and A_(RES) of reservoirs 70 and 80 are circularin shape, have a diameter of D₃ and are all of equal size as shown inFIGS. 3A-3D. In these figures, reservoirs 70, 80 have housings 72, 82that defines the shape of the reservoir and contains electrodes 74, 84and drug-containing gels 76, 86.

In this family of reservoirs, the initial rate of drug delivery will bethe same for reservoirs 70 and 80. However, because of the reducedthickness, T₃, of reservoir 80, it contains less volume of gel and asmaller amount drug and will be able to maintain the same drug deliveryrate as reservoir 70, but for a much shorter period of time.

Another alternative embodiment of the invention is illustrated in FIGS.4A and 4B. Reservoir 90 includes housing 92 that defines the shape ofthe reservoir and contains electrode 94 and drug-containing gel 96.FIGS. 4A and FIG. 4B show reservoir 90 that further includesA_(BODY)-reducing mask 100.

Reservoir 70 has the same diameter as reservoir 90 shown in FIGS. 3B and4B. But because of reducing mask 100, the A_(BODY) and A_(RES) forreservoir 90 are different with A_(BODY) being smaller than A_(RES).Thus with all other factors being the same, including I_(BODY),reservoir 90 will deliver less drug than reservoir 70. It is possiblethat for reservoir 70, the current density will be less than thecritical current density and that for reservoir 90, with the smallerA_(BODY) and the same current, that the current density will be greaterthan the critical current density. If this is the case, then an enhanceddelivery state may occur when reservoir 90 is used and the total drugdelivery may be greater than reservoir 70, even with the reducedA_(BODY).

An additional embodiment of the invention is illustrated in FIG. 5. FIG.5 is a cross-sectional view of reservoir 110 that includes housing 112that defines the shape of the drug reservoir and contains electrode 114,drug-containing gel 116, A_(BODY) reducing mask 118 and inert filler120. Inert filler 120 is shown in FIG. 5 as a spherical element but cantake any convenient form including disks, beads, particles, powder andthe like. One purpose of the inert filler is to reduce the volume ofdrug reservoir 110 without affecting the A_(RES) or thickness thereof.Reservoir 110 is identical to reservoir 90 shown in FIG. 4B, with theexception of the inert filler 120. Thus A_(RES), A_(BODY), and thicknessare the same. However, the total volume of gel in reservoir 110 issmaller and therefore reservoir 110 would be able to deliver drug for ashorter period of time when compared to reservoir 90.

The filler may be wax (e.g., paraffin), polytetrafluoroethylene (e.g.,Teflon®), or other material that does not adversely affect the integrityof the drug contained in the reservoir or the ability of the device todeliver the drug.

Materials suitable for use as the inert filler include, but are notlimited to: glass beads; mineral filler materials, such as titaniumdioxide, talc, quartz powder, or mica; and polymer filler materials.Examples of polymer filler materials are: polymer meshes, such as Saatipolypropylene mesh; polymer powders having particle sizes of betweenabout 1 micron to about 50 micorons, such as micronized polymer waxes ofpolyethylene (e.g., Aqua Poly 250), polypropylene (e.g., Propyltex®140S), polytetrafluoroethylene (e.g., Fluo 300), Fischer-Tropsch waxes(e.g., MP-22C, available from Micro Powders, Inc.) and mixtures thereof;crosslinked polymer beads, such as styrene/divinylbenzene (e.g.,Amberlite® XAD-4 1090 or Amberlite® XAD 16-1090), acrylic/divinylbenzene(e.g., Amberlite® XAD-7) (available from Rohm and Haas), or the like;cellulosic polymers, such as crosslinked dextrans (e.g., Sephadex®)(available from Pharmacia Laboratories); polymer solids having weightaverage molecular weights between about 20,000 and about 225,000, suchas polyvinyl alcohol (e.g., Airvol® 103, available from Air Products;Mowiol® 4-98 and Mowiol® 66-100, available from Hoechst),polyvinylpyrrolidone (e.g., Povidone PVP K-29/32), and mixtures thereof.

An additional embodiment of the invention is illustrated in FIG. 6. FIG.6 is a cross-sectional view of reservoir 130 that includes housing 132that defines the shape of the drug reservoir and contains electrode 134,drug-containing gel 136, and A_(BODY) reducing mask 138. In thisembodiment, electrode 134 functions in a manner similar to the inertfiller 120 shown in FIG. 5.

EXAMPLE 1 Determination of Body Surface-Contact Area forElectrotransport Delivery of Fentanyl

Results from typical calculations on which reservoir configuration maybe based are provided in Table 1 for the drug fentanyl. This table isbased upon a family of reservoirs having the same thickness and the samefentanyl reservoir composition.

For example, to achieve a rate of drug delivery of 150 μg/hr for a drugwith a Rate/i of 1.1 μg/hr/μA and a I_(BODY) of 75 μA/cm², a bodysurface-contact area of 1.82 cm² is required.

This is determined by looking down the “Rate” column until the “150” rowis found. Then move to the right to the middle of the three majorcolumns corresponding to a Rate/i of 1.1. Then within the three columnsunder the 1.1 Rate/i column, find the I_(BODY) column corresponding to75. The value at the intersection of the 150 μg/hr Rate row and theproper column for I_(BODY) and Rate/i is an area of 1.82 cm² for theA_(BODY). Corresponding values can be determined for other values ofRate, Rate/I; and I_(BODY).

If the reservoir thickness is reduced by half, then A_(RES) must beincreased two-fold in order to maintain an adequate drug supply.Therefore, to maintain a minimal I_(BODY) of 75 μA/cm², the A_(BODY)would have to be reduced by half by masking off the reservoir, e.g.,back to an A_(BODY) of 1.82 cm² for the 150 μg/h system, see Table 1.TABLE 1 72-HOUR CHRONIC FENTANYL ELECTROTRANSPORT SYSTEM Rate/i(μg/h/μA) 0.9 1.1 1.3 I_(BODY) (μA/cm²) Rate 50 75 100 50 75 100 50 75100 (μg/hr) A_(BODY) (cm²) 25 0.56 0.37 0.28 0.45 0.30 0.23 0.38 0.260.19 50 1.11 0.74 0.56 0.91 0.61 0.45 0.77 0.51 0.38 75 1.67 1.11 0.831.36 0.91 0.68 1.15 0.77 0.58 100 2.22 1.48 1.11 1.82 1.21 0.91 1.541.03 0.77 150 3.33 2.22 1.67 2.73 1.82 1.36 2.31 1.54 1.15

Using a constant A_(BODY) of 1.82 cm², the thickness of the reservoir iscontrolled by the amount of drug required to provide a predetermineddosage and consequently the volume of the reservoir required to containthe required amount of drug.

As shown in Table 1, the A_(BODY) for a given Rate/i is directlyproportion to the desired rate of drug delivery. Thus, anelectrotransport drug delivery device can be designed comprising aplurality of drug-containing reservoirs each having the same thicknessand an A_(BODY) designed to accommodate a quantity of drug sufficient toachieve a therapeutic effect. The A_(BODY) may be selected to achievethe predetermined dosage at the desired current density using a mask.

EXAMPLE 2 Determination of Electrode Contact Area for ElectrotransportDelivery of Fentanyl

The electrode-reservoir contact surface area (“A_(ELECTRODE)”) may bedetermined based on three parameters:

-   -   a. agent delivery per unit current (which is a property of the        agent);    -   b. the desired electrode current density, I_(ELECTRODE); and    -   c. the desired agent delivery rate.

Table 2 illustrates how these parameters determine the requiredA_(ELECTRODE) for fentanyl. The I_(ELECTRODE) values in Table 2 differfrom the I_(BODY) values provided for fentanyl in Table 1. This is dueto the different requirements for reliable electrochemical operation atthe electrode/gel interface from those requirements for the gel/skininterface. TABLE 2 72-HOUR CHRONIC FENTANYL ELECTROTRANSPORT SYSTEMRate/i (μg/h/μA) Deliv- 0.9 1.1 1.3 ery I_(ELECTRODE) (μA/cm²) Rate 4050 75 40 50 75 40 50 75 (μg/hr) A_(ELECTRODE) (cm²) 25 0.69 0.56 0.370.57 0.45 0.30 0.48 0.38 0.26 50 1.39 1.11 0.74 1.14 0.91 0.61 0.96 0.770.51 75 2.08 1.67 1.11 1.70 1.36 0.91 1.44 1.15 0.77 100 2.78 2.22 1.482.27 1.82 1.21 1.92 1.54 1.03 150 4.17 3.33 2.22 3.41 2.73 1.82 2.882.31 1.54

The choice of I_(ELECTRODE) is also influenced by the drug compositionand amount of the drug formulation in the reservoir. For example, as theA_(RES) is decreased to accommodate a particular volume of drugformulation, the A_(ELECTRODE) may be reduced as well. For an amount ofcurrent required to deliver an agent at a predetermined rate, theI_(ELECTRODE) will increase as the A_(ELECTRODE) decreases. As theI_(ELECTRODE) increases, the electrochemical reaction that takes placeat the electrode-reservoir interface will require more counter ions toprevent silver migration and the oxidation of water in the formulation,which will change the pH of the formulation and the ionic nature of theagent, or oxidation of the agent itself. In order to maintain theI_(ELECTRODE) below a level at which such undesirable side effects mayoccur, the A_(ELECTRODE) must be maintained above a minimum level. Inorder to increase the A_(ELECTRODE), the A_(RES) may have to be largerthan the A_(BODY) that is required to maintain a minimal I_(BODY). Thus,the reservoir would have to be “masked down” to reduce the A_(BODY) andincrease the I_(BODY) above the minimal I_(BODY).

Alternatively, the A_(ELECTRODE) can be increased by using an electrodethat is fabricated to have a greater surface area, e.g., having acorrugated surface, or being U-shaped, in which case the electrode wouldbe embedded in the reservoir rather than on the surface thereof (seeFIG. 6).

Using an embedded electrode as shown in FIG. 6 is also useful when anoverall increase in drug delivery is desired. For example, if the drugdelivery rate from a reservoir having the configuration as shown in FIG.4B were to be increased several fold, the total current i would have tobe increased. If no other changes were made, this would result in anincrease in the I_(ELECTRODE), potentially to the level at whichundesirable electrochemical reactions would occur at the electrode. Thisproblem can be solved by increasing the A_(ELECTRODE) to a size that theI_(ELECTRODE) falls below the problematic level. The A_(ELECTRODE) caneasily be increased by simply increasing its size so that it is the samesize as the A_(RES). However, if A_(ELECTRODE) needs to be larger thanA_(RES), in order that I_(ELECTRODE) be still smaller, then theelectrode will need to project into the reservoir as shown as in FIG. 6.

EXAMPLE 3 Family of Reservoirs having Different Delivery Rates

In the treatment of chronic pain, the phenomenon of requireddose-escalation over time in order to alleviate the same level of painis often experienced by those using narcotic analgesics (e.g., morphineand its analogues, fentanyl and its analogues). This phenomenon requiresthat the dosage be increased over time to achieve an equivalent degreeof pain relief. What is described in this example are two members of afamily of two or more reservoirs which provide for identical reservoirssizes, essentially identical reservoir housings and identical reservoircompositions. This provides an easy way to select a one of severaldosage delivery rates by attaching one of the family of reservoirs tothe same controller. As will be discussed, the control is a smartcontroller which recognizes the particular drug reservoir that has beenattached to the controller.

Two members of a family of reservoir are shown in FIGS. 7A and 7B. Eachof these two reservoirs is identical in all respects with the exceptionof Mask 148, which is not present in FIG. 7A and is present in FIG. 7B.

Assuming a typical body current density, I_(BODY), of 100 microamps/cm²,and a body contact area, A_(BODY), of 1 cm², a current of 100 microampswould be required. If one wanted to decrease the rate of drug delivery,then one could decrease the body contact area, A_(BODY) as long as theI_(BODY) was maintained the same. One way would be to make a reservoirhaving a smaller A_(RES) and a correspondingly smaller A_(BODY). Thedrawback to this approach is that a number of other factors would haveto be changed including the diameter and thickness of the reservoirs,and all the concomitant changes in manufacturing and assembly that wouldbe required to produce this reservoir. To maintain the same overall drugcapacity, the reservoir would have to be thicker to accommodate agreater volume of drug formulation.

An alternative is to utilize the reservoir configuration changes shownin FIG. 7B. In this reservoir, the body contact area, A_(BODY), isreduced by inclusion of Mask 148, which effectively reduces the actualcontact area of the reservoir, A_(RES), by masking off a portion of itbehind the insulating layer of Mask 148. Other than the inclusion of themask, the reservoirs of FIGS. 7A and 7B are the same.

Let's assume that Mask 148 in FIG. 7B reduces the contact area by onehalf. To maintain the I_(BODY) at the desired level of 100microamps/cm², the current delivered by the controller must be reducedby half. Though not shown here, there are a number of techniques bywhich a controller could sense which of several reservoirs was beingattached and adjust the current level corresponding to that particulardrug reservoir unit.

The great benefit from this system is that a great majority of thephysical parameters of the reservoir and the reservoir composition areall the same. This enables the reservoirs to be highly optimized interms of volume, A_(RES), A_(ELECTRODE), I_(BODY), I_(ELECTRODE), andreservoir formulations, but at the same time provide a series of drugreservoirs from which can be selected the particular reservoir that fitsthe needs of a particular patient. Although this embodiment has beendescribed with reference to two reservoirs, the inventive concept can,in the same manner, be applied to a family having any number ofreservoirs.

Thus, the invention provides a novel therapeutic agent-containingreservoir for use in an electrotransport drug delivery device and asystem comprising a plurality of classes of such reservoirs. Althoughpreferred embodiments of the subject invention have been described insome detail, it is understood that obvious variations can be madewithout departing from the spirit and the scope of the invention asdefined by the appended claims.

1. A method for administering an effective amount of a therapeutic agentto a patient in need of such treatment by electrotransport comprising:selecting an effective dosage and delivery rate of at least onetherapeutic agent for a patient; providing an electrotransportcontroller for delivering a pre-selected current output, the controllerincluding a coupler for attaching and communicating to a reservoircontaining a therapeutic agent; selecting a reservoir from a family ofreservoirs, each reservoir having at least a predetermined quantity of atherapeutic agent sufficient to achieve the effective dosage of theagent wherein each of the reservoirs has body contacting surface areadifferent from the body contacting surface area of another reservoir inthe family, said reservoirs each having a coupler for communicativelyattaching to said controller and an electrode; coupling the selectedreservoir to the controller so that said output is in electrical contactwith the electrode of the selected reservoir so that the reservoir iscommunicatively attached to said controller to provide anelectrotransport delivery system; placing the body contacting surfacearea of the selected reservoir in electrical contact with the skin ofthe patient to provide the selected effective dosage and delivery ratefor the patient; and activating the electrotransport delivery system toadminister the therapeutic agent to the patient through the skinsurface.
 2. The method of claim 1 further comprising providing a signalfrom the selected reservoir to the controller related to the dosage ofthe therapeutic agent to be delivered, the controller selecting acurrent output in response to the signal.
 3. The method of claim 2wherein the signal is selected from the group consisting of acapacitance signal, an optical signal and a coded electromechanicalsignal.
 4. The method of claim 1 wherein placing the body contactingsurface area of the selected reservoir in electrical contact with theskin further comprises applying said electrotransport device to thepatient's skin by application of a sufficient pressure to adhere aselectively removable biocompatible adhesive surface to the patient'sskin so that the body contacting surface of each of the selectedreservoir is in substantially uniform electrically conductive contactwith the patient's skin and said electrotransport system is retained onthe skin.
 5. The method of claim 1 wherein said activating step furthercomprises pressing on a momentary contact switch, thereby causing thecontroller to begin delivering the effective amount of therapeutic agentto the patient.
 6. The method of claim 5 wherein activating theelectrotransport delivery system further comprises noticing aconfirmation signal from said controller.
 7. The method of claim 6wherein said the confirmation signal is selected from the groupconsisting of an audible tone, a visible light and a combinationthereof.
 8. The method of claim 1 further comprising transmitting theoutput of the controller to the electrode of the reservoir by releasablyelectrically attaching the output of the controller with a pressuresensitive electrically conductive adhesive.
 9. The method of claim 1wherein of selecting an effective dosage of at least one therapeuticagent further comprises selecting a different therapeutic agent for eachreservoir in the family.
 10. The method of claim 1 wherein the bodycontacting surface area of at least one of the reservoirs is adjustable.11. The method of claim 9 wherein said step of selecting said differenttherapeutic agent for each reservoir further comprises selecting fromsaid controller a first delivery output to one of the reservoirs and asecond delivery output to another of the reservoirs, so that differentthe therapeutic agents selected for each reservoir can be delivered inan effective amount for each agent.
 12. The method of claim 1 whereinsaid step of selecting an effective dosage of at least one therapeuticagent further comprises selecting the same therapeutic agent for eachreservoir.
 13. The method of claim 12 wherein the body contactingsurface area of at least one of the reservoirs is adjustable.
 14. Themethod of claim 13 wherein providing an electrotransport controller fordelivering a pre-selected current output from said controller furthercomprises selecting a first delivery output to one of the family ofreservoirs and a second delivery output to another of the familyreservoirs, so that one pre-selected delivery rate of the dosage fromone reservoir can be supplemented by an another output dose deliveryrate from the other reservoir.
 15. The method of claim 1 furthercomprising removing said electrotransport system from the skin of thepatient when said administering step of the selected dose is completed.16. The method of claim 15 further comprising separating the selectedreservoir from the controller; cleaning said controller; attaching anunused reservoir having at least a predetermined quantity of atherapeutic agent sufficient to achieve a pre-selected therapeuticdosage of the agent to the controller rendering the electrotransportsystem ready for reuse.
 17. The method of claim 1, wherein thetherapeutic agent is selected from the group consisting of fentanyl,sufentanil and salts thereof.